THPO promoter mutation: a familial study on congenital amegakaryocytic thrombocytopenia

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome, which is characterized by a severe thrombocytopenia at birth without predictive stigmata and by a risk for progression into aplastic anaemia and myeloid malignancy. While CAMT primarily arises from mutations in the MPL gene, recent discoveries have linked biallelic THPO mutations to some CAMT cases. In addition, loss of function monoallelic mutations in this gene have been identified as causing benign autosomal dominant thrombocytopenia. In this study, we report a case of CAMT linked to a homozygous mutation in the promoter region of THPO (c.-324C>T, NM_000460.4). computational analysis indicates that this mutation suppresses the binding of some essential transcription factors to the THPO promoter. Family segregation analysis shows a significant reduction in platelet counts among carriers of the mutation. Our patient received allogeneic haematopoietic stem cell transplantation (HSCT) from her HLA-matched sister (MSD), who carries the mutation. After allogeneic HSCT, the patient showed 100% full donor chimerism, but 1 year after HSCT, despite full donor chimerism, the patient did not complete recover from platelet count, and she has received romiplostim several times. Understanding the MPL-THPO pathway is vital for managing CAMT, emphasizing the importance of identifying and assessing patients' mutations for tailored treatment.